Obstructive sleep apnea is a prevalent disorder associated with significant cardiovascular and neurological morbidity. One of the most common and troubling neurobehavioral sequelae is residual sleepiness in patients treated for obstructive sleep apnea. During the previous award period, we established that oxygenation patterns modeling severe sleep apnea (long-term intermittent hypoxia, LTIH) result in irreversible wake impairments and injury to catecholaminergic wake neurons. Also, in the previous award period we identified NADPH oxidase (Nox2) as a key source of neuronal injury and apoptosis. A next important step is to establish direct effects of LTIH on the function of catecholaminergic wake neurons and to establish whether Nox2 contributes to LTIH effects on wake neuron function (Aim 1). LTIH mechanisms of injury in cell culture extend beyond Nox2 activation to include mitochondrial injury and reduced superoxide dismutase activity. We have begun to explore endogenous protective pathways to counter all LTIH injuries, one that could be augmented to prevent or treat injuries clinically, ultimately. SIRT1 is a redox sensitive deacetylase that executes a comprehensive anti-oxidant response, including up-regulation of anti-oxidant enzymes and optimization of mitochondrial configuration and number to reduce mitochondrial superoxide production. Recently, we identified SIRT1 in wake neurons and established critical functional and neuroprotectant roles for SIRT1 in wake neurons under normoxic conditions. A next step is to integrate these findings with our LTIH work and determine whether LTIH impairs the SIRT1 activation and whether reduced SIRT1 accentuates injury and behavioral effects of LTIH (Aim 2). In addition to examining the impact of insufficient SIRT1 activation on catecholaminergic wake neuron function and wakefulness, we are poised to begin translating our findings to explore whether transgenic augmentation of SIRT1 activity can prevent or partially reverse wake neuron injuries and impaired wakefulness in LTIH (Aim 3). PUBLIC HEALTH RELEVANCE: Sleepiness, fatigue and impaired cognition are major problems for individuals with obstructive sleep apnea, a disorder affecting 8-10 million Americans. The proposed studies will significantly advance the mechanisms underlying impaired alertness in sleep apnea, and are expected to unveil novel therapeutic approaches to prevent or reverse impaired cognition and neuronal injury in sleep apnea.